Light, sleep and circadian interactions: biology to new therapeutic targetsLight, clocks and sleep: clinical implications and new therapeutics

Abstract

Presentation Description : By studying how circadian rhythms and sleep are regulated by the dawn/dusk cycle we demonstrated the existence of a “3rd class” of photoreceptor within the eye based upon a small number of photosensitive retinal ganglion cells (pRGCs) that utilise the blue light sensitive photopigment melanopsin (OPN4). Whilst there has been remarkable progress in understanding the complex intracellular mechanisms that generate circadian rhythms, the molecular pathways whereby the pRGCs entrain circadian biology and sleep has remained poorly understood. The suprachiasmatic nuclei (SCN) are the site of the primary circadian pacemakers within the mammalian brain. Until recently, the model for entrainment involved a simple linear pathway whereby glutamate release from the pRGCs resulted in Ca²⁺ influx and raised intracellular cAMP in SCN neurones, which in turn resulted in CREB phosphorylation leading to increased transcription of two key clock genes, Per1 and Per2. This signal then advanced or delayed the molecular clockwork. However, an important feature of entrainment is that circadian responses to light are limited – as typified by jet-lag. Full recovery from jet-lag requires a day for every time-zone crossed. We addressed this issue and have identified and characterized a key role for Salt Inducible Kinase 1 (SIK1) and the CREB-regulated transcription co-activator 1 (CRTC1) in clock re-setting. In addition, our more recent and unpublished findings have shown that light entrainment also involves the parallel activation of a Ca²⁺-ERK1/2-AP-1 signalling pathway. Thus both CRE and AP-1 regulatory elements drive light-induced clock gene expression. These findings led to further insight into how sleep/wake history, encoded by levels of adenosine, modulates the effects of light upon the molecular clockwork by interacting with Ca²⁺-ERK1/2-AP1 and CREB/CRTC1-CRE signalling pathways. Finally, the presentation will explore how such signalling mechanisms provide a potentially new target for the regulation of circadian rhythms and the “pharmacological” replacement of light for sleep/wake re-setting in individuals lacking eyes or other individuals with severe circadian rhythm disruption.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.